Multiple sclerosis (MS) is one of the inflammatory demyelinating diseases of central nervous system and is characterized by multiple occurrence in terms of time and space. In Japan, there are about 10,000 patients suffering from the disease, and thus the disease is a rare disease and is designated as an intractable disease. Japan Intractable Diseases Information Center administered cooperatively by Ministry of Health, Labour and Welfare, Health Service Bureau, Diseases Control Division and Japan Intractable Diseases Research Foundation defines multiple sclerosis as follows:
The cause of multiple sclerosis has not been clarified. In general, infiltration of lymphocytes and macrophages into nerve tissue is observed, and from the blood biochemical viewpoint, drastic increase in blood IgG with respect to the total proteins is observed, so that the disease is thought to be caused by inflammation mechanism. However, since a specific pathogen such as a virus is not found in the site of inflammation, it has been suggested that autoimmune mechanism is involved in the formation of lesions. Although myelin basic protein (MBP) level raises in some cases reflecting the collapse of myelin, it is not specific to multiple sclerosis. The symptoms of multiple sclerosis differ depending on the damaged site in the nervous system, and visual disorders, diplopia, cerebellar ataxia, quadriplegia, sensory disturbances and the like are observed (for example, Non-patent Literature 1).
One of the sensory disturbances is severe pruritus (itching), and the pruritus emerges in cases where the dorsal horn of the spinal cord is damaged (for example, Non-patent Literature 2). The pruritus is characterized by the fact that pruritus lasting several minutes occurs spasmodically several times a day. The favorite sites of the pruritus are relatively bilateral in accordance with the segments of innervation by cervical and thoracic nerves. The feeling of the pruritus is unbearable itching like that felt after insect bite by a small insect. If the pruritus occurs in night, sleep is disturbed (for example, Non-patent Literature 3). Although no eruption is observed on the skin, the skin sometimes has erosions due to vigorous scratching. In most cases, the pruritus is observed at the initial stage in the advanced stage. Although the generated pruritus is reduced once, it lasts many years. There are cases where the pruritus is induced by a touch on the skin. Antihistamines have almost no effects against the pruritus. Since it has been confirmed that some of the drugs which inhibit neuronal firing, such as carbamazepine, phenyloin and mexiletine are partly effective for the pruritus, it has been suggested that the pruritus accompanied by multiple sclerosis is different from ordinary pruritus. Although it has been reported that steroid pulse therapy in which a large amount of a steroid is administered by drip infusion for 3 to 5 days is effective (for example, Non-patent Literature 4), the therapy requires hospitalization for treatment, and many side effects caused by the systemic administration of the steroid, such as infections, digestive ulcers, obesity, diabetes, osteoporosis and mood disorder, are problematic (Non-patent Literature 5). Dermatologists express the pruritus as a strange symptom, which pruritus cannot be stopped by scratching and which may lead to a damage of skin by scratching, that can be called a self-injurious behavior (for example, Non-patent Literature 2).
In spite of the fact that the pruritus caused by multiple sclerosis is very uncomfortable and is a symptom which reduces quality of life, the mechanism is unclear and effective therapeutic method has not been established, which is a big problem in medicine. Development of a more effective therapeutic drug is strongly demanded.
In recent years, it has been suggested that agonist compounds for the κ opioid receptor which is one of the opioid receptors have antipruritic activities (for example, Non-patent Literature 6). It has been reported that κ opioid receptor agonist compounds having 4,5-epoxymorphinan skeleton may be used as an antipruritic for general prurituses accompanied by, for example, dermatoses such as atopic dermatitis, neurodermatitis, contact dermatitis, seborrheic dermatitis, autosensitization dermatitis, caterpillar dermatitis, asteatosis, senile pruritus cutaneous, insect sting, photosensitive dermatitis, urticaria, prurigo, herpes, impetigo, eczema, tinea, lichen, psoriasis, scabies and acne vulgaris; and visceral diseases such as malignant tumors, diabetes mellitus, hepatic diseases, renal failure, renal dialysis and pregnancy (for example, see Patent Literature 1).
However, whether or not the κ opioid receptor agonist compounds are effective for pruritus caused by multiple sclerosis was unknown, which is a neurological disorder and not a dermatosis or internal disease, the characteristics and therapies for the pruritus being largely different from normal pruritus.    Patent Literature 1: Japanese Patent Publication No. 3531170    Non-patent Literature 1: Neuromuscular Disorders Research Group (immunologic nuerological diseases) “Guidelines for Diagnosis and Therapy>multiple sclerosis” [online] Jun. 20, 2005, Japan Intractable Diseases Information Center, [searched on Feb. 27, 2006], internet <http://www.nanbyou.or.jp/sikkan/068_i.htm>    Non-patent Literature 2: Kiyoharu INOUE, “Sogo Rinsho” (Japan), 2004, Vol. 53, No. 5, p. 1807-1811    Non-patent Literature 3: Yoshiki MIYAJI eds., “Pruritus Q & A”, (Japan), First Edition, Iyaku (Medicine and Drug) Journal Co., Ltd., 1997, p. 86-87    Non-patent Literature 4: Kiyoharu INOUE, “Japan Medical Journal” (Japan), 2003, Vol. 4157, p. 85    Non-patent Literature 5: Takashi YAMAMURA (editor, National Center of Neurology and Psychiatry, National Institute of Neuroscience), “Outlines of Multiple Sclerosis”, [online], March, 2004, Specified Nonprofit Corporation MS CABIN, searched on Feb. 27, 2006, internet <http://www.mscabin.org/ms08.html>    Non-patent Literature 6: European Journal of Pharmacology, (Netherlands), 2002, Vol. 435, No. 2-3, p. 259-264